Peripheral nerves are well-organized composite tissues that exist in a dynamic biomechanical environment created by the movement of articulating joints. To accommodate mechanical loads, nerves glide and stretch within their beds. Nerve entrapment alters the structure of nerves, restricts their ability to glide, and excessively increases regional deformation, ultimately impairing sensory and motor function. The most common entrapment neuropathy among Veterans is carpal tunnel syndrome (CTS), a disease in which the median nerve is impinged at the wrist, within the carpal tunnel. Surgical treatment of carpal tunnel syndrome is generally effective, but revision may be required for 3-20% of surgeries. Given the prevalence of CTS, this corresponds to a substantial number of patients. Electrodiagnostics are considered to be the gold standard for CTS diagnosis, inconclusive outcomes are not uncommon, especially in the presence of other overlying neuropathies, such as diabetic neuropathy. Despite their likely influence on neuropathic progression, nerve structural and biomechanical changes have been used only minimally to diagnose or track neuropathy, or to assess the efficacy of surgical management. This is in large part due to the challenges associated with imaging nerves using current techniques. Our research team has developed new magnetic resonance imaging (MRI) and ultrasound-based imaging methods that allow the visualization of nerves at high spatial resolution on contrast. These capabilities allow accurate measurement of nerve biomechanics (deformation and stiffness), and also identification and quantitative characterization of structural elements within nerves. These methods are expected to provide a powerful and sensitive approach to non-invasively assess neuropathy and surgical efficacy. Given its prevalence, CTS provides an ideal test-bed for translating our nerve imaging and image processing techniques to a clinical setting. In particular, we propose to use ultrasound and MRI techniques to evaluate structure and biomechanics of median nerves in patients requiring surgery for CTS. Our proposal uses a multi-disciplinary approach to address two specific aims. Our first aim is to optimize MRI-based and ultrasound imaging methodology in median nerves. We will use human cadaveric and in vivo models to validate and optimize imaging protocols that will be used clinically. We expect that MRI-based strategies will provide high resolution and high contrast structural images of nerves, while ultrasound will provide rapid assessment of nerve kinematics and stiffness. Our second aim is to examine structural and kinematic changes of median nerves in patients with CTS, before and after carpal tunnel release, using MRI and ultrasound. We hypothesize that MRI-based imaging will detect structural differences in epineurial, perineurial, and nerve fiber compartments between control and entrapped nerves, and ultrasound will detect differences in nerve deformation and stiffness among control nerves and entrapped nerves before and after surgery. More broadly, we anticipate applying our approach to other neurological conditions that impact the Veteran healthcare system, in which nerve structure and biomechanics may be altered. These include other entrapment neuropathies, diabetic neuropathy, and traumatic nerve injury. Ultimately, successful execution of our proposed study will enable earlier recognition of neuropathy, provide noninvasive monitoring of neuropathic progression, and facilitate more accurate assessment of rehabilitative and therapeutic efficacy. 1